The complement system links platelet activation to inflammation

补体系统将血小板激活与炎症联系起来

• 批准号: 8391550
• 负责人: ROLANDO E RUMBAUT
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391550
• 关键词: Abnormal Platelet; Alternative Complement Pathway; Bacterial Toxins; Binding; Blood Clot; Blood Platelets; Blood Vessels; Blood coagulation; C5a anaphylatoxin receptor; Cause of Death; Coagulation Process; Complement; Complement Factor H; Complement Receptor; Complication; Data; Defect; Deposition; Disease; Employee Strikes; Functional disorder; Funding; Goals; Immune response; Infection; Inflammation; Inflammation Process; Inflammatory; Inflammatory Response; Integrins; Intensive Care Units; Kinetics; Laboratories; Link; Measures; Mediating; Mediator of activation protein; Medical; Modeling; Morbidity - disease rate; Mus; Organ; Outcome; Pathogenesis; Patients; Plasma; Platelet Activation; Platelet aggregation; Process; Protocols documentation; Research; Role; Sepsis; Surface; System; Therapeutic; Thrombosis; Time; United States; Veterans; Work; complement deficiency; complement pathway; complement system; improved; in vivo; intravital microscopy; mortality; new therapeutic target; programs; receptor; research study; response

The interactions between the processes of inflammation and thrombosis are increasingly recognized as relevant to the pathogenesis of various diseases. A striking example of these interactions is evident in sepsis, a systemic inflammatory response to an infection. Sepsis is the leading cause of death in non-cardiac intensive care units in the United States, and microvascular thrombosis is a significant complication in sepsis. One aspect of the inflammatory response in sepsis involves the complement system, an integral part of the innate immune response. Recent data demonstrate that the complement system may provide a link between inflammation and thrombosis; this application will help understand the mechanisms involved in these interactions, with a particular emphasis on sepsis. The central hypothesis is that platelet-associated components of the complement system provide a link between inflammation and thrombosis in sepsis. The proposal will utilize genetically targeted complement deficient mice and their relevant controls to assess platelet function ex vivo and in vivo. Ex vivo experiments involve measures of platelet aggregation, and protocols to distinguish intrinsic platelet defects from effects due to complement factor deposition on platelets. In vivo experiments will utilize an intravital microscopy model of microvascular thrombosis, which allows assessment of the kinetics of platelet-microvessel interactions in real-time. Some experiments will use passive transfer of platelets to determine whether a platelet-bound complement receptor is sufficient to mediate the role of this receptor in microvascular thrombosis. Two aims are proposed: Aim 1 will determine which complement pathways and platelet-associated components of the complement system mediate abnormal platelet function in complement deficient mice. Aim 2 will determine the role of components of the complement system in microvascular thrombosis in experimental sepsis. Completion of these aims will broaden understanding of the role of the complement system as a link between inflammation and thrombosis, with an emphasis on sepsis.

炎症和血栓形成过程之间的相互作用越来越多 被认为与各种疾病的发病机制有关。其中一个突出的例子是 相互作用在脓毒症中是明显的，脓毒症是对感染的全身炎症反应。脓毒症是 是美国非心脏重症监护病房的主要死亡原因， 微血管血栓形成是脓毒症的重要并发症。的一个方面 脓毒症中的炎症反应涉及补体系统，补体系统是脓毒症的组成部分。 先天免疫反应最近的数据表明，补体系统可以提供 炎症和血栓形成之间的联系;这个应用程序将有助于了解 机制参与这些相互作用，特别强调败血症。中央 假设是补体系统的血小板相关成分提供了一种联系 炎症和血栓之间的联系该提案将利用基因靶向 补体缺陷小鼠和它们的相关对照以评估离体和体内血小板功能 vivo.离体实验涉及血小板聚集的测量，以及 区分内在的血小板缺陷和补体因子沉积对 血小板体内实验将利用微血管的活体显微镜模型。 血栓形成，这允许评估血小板-微血管相互作用的动力学， 实时的一些实验将使用血小板的被动转移来确定 血小板结合补体受体足以介导该受体在 微血管血栓形成提出了两个目标：目标1将确定 补体系统的途径和血小板相关成分介导异常的 补体缺乏小鼠的血小板功能。目标2将确定 补体系统在实验性脓毒症微血管血栓形成中的作用完成 这些目标将扩大对补体系统作为连接 炎症和血栓形成，重点是败血症。

项目成果

The β isoform of the catalytic subunit of protein phosphatase 2B restrains platelet function by suppressing outside-in αII b β3 integrin signaling.

• DOI: 10.1111/jth.12761
• 发表时间: 2014-12
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: Khatlani T;Pradhan S;Da Q;Gushiken FC;Bergeron AL;Langlois KW;Molkentin JD;Rumbaut RE;Vijayan KV
• 通讯作者: Vijayan KV

Polymicrobial sepsis and endotoxemia promote microvascular thrombosis via distinct mechanisms.

• DOI: 10.1111/j.1538-7836.2010.03853.x
• 发表时间: 2010-06
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: Patel KN;Soubra SH;Lam FW;Rodriguez MA;Rumbaut RE
• 通讯作者: Rumbaut RE